Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, USA.
Dev Dyn. 2010 Jan;239(1):327-37. doi: 10.1002/dvdy.22156.
Robinow syndrome is a skeletal dysplasia with both autosomal dominant and autosomal recessive inheritance patterns. It is characterized by short stature, limb shortening, genital hypoplasia, and craniofacial abnormalities. The etiology of dominant Robinow syndrome is unknown; however, the phenotypically more severe autosomal recessive form of Robinow syndrome has been associated with mutations in the orphan tyrosine kinase receptor, ROR2, which has recently been identified as a putative WNT5A receptor. Here, we show that two different missense mutations in WNT5A, which result in amino acid substitutions of highly conserved cysteines, are associated with autosomal dominant Robinow syndrome. One mutation has been found in all living affected members of the original family described by Meinhard Robinow and another in a second unrelated patient. These missense mutations result in decreased WNT5A activity in functional assays of zebrafish and Xenopus development. This work suggests that a WNT5A/ROR2 signal transduction pathway is important in human craniofacial and skeletal development and that proper formation and growth of these structures is sensitive to variations in WNT5A function.
罗宾诺综合征是一种骨骼发育不良症，具有常染色体显性遗传和常染色体隐性遗传两种遗传模式。其特征为身材矮小、四肢短小、生殖器发育不全和颅面畸形。显性罗宾诺综合征的病因不明；然而，表型上更为严重的常染色体隐性罗宾诺综合征与孤儿酪氨酸激酶受体 ROR2 的突变有关，最近已将其鉴定为潜在的 WNT5A 受体。在此，我们展示了两种不同的 WNT5A 错义突变，这些突变导致高度保守半胱氨酸的氨基酸取代，与常染色体显性罗宾诺综合征有关。一种突变存在于 Meinhard Robinow 最初描述的家族中所有在世的受影响成员中，另一种突变存在于第二个无关的患者中。这些错义突变导致在斑马鱼和非洲爪蟾发育的功能测定中 WNT5A 活性降低。这项工作表明，WNT5A/ROR2 信号转导途径在人类颅面和骨骼发育中很重要，这些结构的正常形成和生长对 WNT5A 功能的变化很敏感。
